Human reproduction is complex and not very efficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation due to an inadequate uterine milieu. Unwanted pregnancy loss is a major psychological, economical and clinical problem. One prerequisite for implantation in placental mammals is an effective two-way interaction between an implantation- competent blastocyst and the receptive uterus. The blastocyst will implant only when this molecular dialogue is established. The underlying mechanism by which a uterus transits from the pre-receptive to the receptive to the non-receptive phase remains unknown. We hypothesize that two highly conserved genes (Msx1 and Msx2) of the muscle segment homeobox (Msh) family have key roles in uterine receptivity and non-receptivity to implantation. In the proposed study, we will test the hypothesis that these morphogenetic genes, critical for epithelial-mesenchymal interactions during development, also play crucial roles in implantation by altering the epithelial cell polarity and integrity via a non- canonical Wnt signaling involving E-cadherin-2-catenin complex formation. To test our hypothesis, we will pursue two specific aims in mice. The first specific aim will test the hypothesis that while Msx1 is a major critical factor in implantation, Msx2 has a compensatory role if Msx1 is missing. The second specific aim will test the hypothesis that Msx1 and/or Msx2 direct implantation by influencing the epithelial cell polarity and integrity. The overall goal of this proposal is to better understand the mechanisms that direct uterine receptivity and non-receptivity with the aim of improving female fertility. We will use conditionally gene-deleted mouse models to address the molecular basis of these events, since these models provide mechanistic information relevant to female fertility which cannot be pursued in humans due to ethical restrictions. However, we will collaborate with clinician scientists to determine clinical correlates of our findings in mice.